The enteroinsulinar axis hypothesis proposes that enteric endocrine factors released from the gastrointestinal tract after ingestion of a meal play a major role in the stimulation of pancreatic insulin secretion. The secretion of this factor(s), as well as its insulin-releasing action is triggered by ingestion of certain nutrients, especially carbohydrates. The gut insulinotropic factor is called incretin and it is probably a peptide. The function of an incretin, in part, is to facilitate glucose homeostasis by anticipating the glucose surge in plasma after ingestion. We have demonstrated that a recently isolated mammalian gut peptide, gastrin releasing peptide (GRP) is a potent insulinotropic peptide. Preliminary data indicate that the insulinotropic action GRP is nutrient dependent. The long-term objective of the proposed research is to test the hypothesis that GRP plays an important role, as an incretin, in the regulation of pancreatic insulin secretion. The specific aims of this research proposal include the following: 1) to characterize the insulinotropic action of the mammalian non-antral stomach peptide, gastrin-releasing peptide (GRP); 2) to examine the regional distribution of immunoreactive GRP-like peptides and to characterize the molecular forms of GRP-like peptides in the gut; 3) to examine and characterize the heterogeneity of immunoreactive GRP-like peptides in plasma; 4) to characterize the insulinotropic potency of gut GRP-like peptides using an insulinoma cell line. While completing the proposed studies, we will characterize the insulinotropic action of GRP, as well as determine the immunoreactive variants of GRP present in plasma and gut tissue during various metabolic states. Completion of these studies will clarify the role of GRP in the physiologic regulation of insulin secretion. Such information is important to a better understanding of the role enteric factors play in the regulation of the endocrine pancreas in humans.